Benzimidazole derivatives

ABSTRACT

This invention provides compounds having the structure:                    
     wherein each of R 1 , R 2 , R 3  and R 9  is independently H; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; wherein each dashed line represents a single bond or a double bond with the proviso that if R 1  is present, R 3  is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R 3  is present, R 1  is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; wherein each of R 4 , R 5  and R 6  is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, —OH, —OR 7 , —CN, —COR 7 , —CO 2 R 7 , —CON(R 7 ) 2 , —OCOR 7 , —SR 7 , —N(R 7 ) 2 , —NR 7 COR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n N(R 7 ) 2 , —(CH 2 ) n NR 7 COR 7 , wherein n is an integer from 1 to 4; and wherein each of R 7  and R 8  is independently H; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; phenyl or substituted phenyl. 
     These compounds are selective for cloned human alpha 2 receptors and are useful as analgesic, sedative or anaesthetic agents.

BACKGROUND OF THE INVENTION

This application is a continuation of U.S. Ser. No. 09/232,490, filedJan. 15, 1999, U.S. Pat. No. 6,316,637, which is a continuation of U.S.Ser. No. 08/765,656, filed Mar. 25, 1997, now abandoned, which was a§371 national stage application of PCT International Application No.PCT/US95/09895, filed Aug. 4, 1995 on behalf of Synaptic PharmaceuticalCorporation, claiming priority of and a continuation-in-part of U.S.Ser. No. 08/285,956, filed Aug. 4, 1994, now abandoned, the contents ofall of which are hereby incorporated by reference into this application.Throughout this application, various references are referred to withinparenthesis. Disclosure of these publications in their entireties arehereby incorporated by reference into this application to more fullydescribe the state of the art to which this invention pertains.

Alpha adrenergic receptors are plasma membrane receptors which arelocated in the peripheral and central nervous systems throughout thebody. They are members of a diverse family of structurally relatedreceptors which contain seven putative helical domains and transducesignal by coupling to guanine nucleotide binding proteins (G-proteins).These receptors are important for controlling many physiologicalfunctions and, thus, have been important targets for drug developmentduring the past 40 years. Examples of alpha adrenergic drugs includeclonidine, phenoxybenzamine and prazosin (for treatment ofhypertension), naphazoline (for nasal decongestion), medetomidine (forveterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma).However, most of these drugs produce undesirable side effects which maybe due to the their interactions with other receptor subtypes. Forexample, clonidine is a well known centrally acting antihypertensiveagent. However, it also produces untoward side effects such asanalgesia, sedation, bradycardia and dry mouth which may be due to itslack of selectivity for a specific receptor subtype, i.e. α₂ receptor.

Alpha adrenoceptors were originally proposed to have only two (alpha andbeta) subtypes (Berthelsen, S.; Pethinger W. Life Sci. 1977, 21, 595).However, modern molecular biological and pharmacological techniques haveled to the identification of at least 6 subtypes (α_(1a), α_(1b),α_(1c), α_(2a), α_(2b) and α_(2c)) of the adrenoceptors (Bylund, D. B.,Trends Pharmacol. Sci. 1988, 9, 356; Weinshank et al, U.S. Pat. No.5,053,337, issued Oct. 1, 1991; Bard et al, International PublicationNo. WO 94/08040, published Apr. 14, 1994).

Among many other therapeutic indications, α₂ receptors are believed tomodulate pain and behavioral depression by regulating locus coeruleusfiring. In addition, α₂ receptors are well known to be involved ineffects on blood pressure, heart rate, vasoconstriction and glaucoma.However, it is not known which therapeutic indications are controlled byeach of these subtypes.

The effects of alpha-2 receptor agonists on analgesia, anesthesia andsedation have been well documented for past 10 years (Pertovaara, A.,Progress in Neurobiology, 1993, 40, 691). For example, systematicadministration of clonidine has been shown to produce antinociception invarious species including human patients in addition to its well knownsedative effects. Intrathecal and epidural administration of clonidinehas also proved effective in producing antinociception. Another alpha-2agonist, Medetomidine, which has better alpha-2/alpha-1 selectivity andis more potent at alpha-2 receptors than clonidine, has been extensivelystudied for its antinociception effect. In the spinally-initiatedheat-induced tail flick test in rats, systematic administration ofmedetomidine produced a dose-dependent antinociception which could betotally reversed by alpha-2 receptor antagonists, atipamazole oridazoxan. Experimental studies of medetomidine on pain sensitivity inhumans also indicated that this agent is very effective on ischemicpains, even though effective drug doses were high enough to produce asedation and considerable decrease in blood pressure.

Effects of alpha-2 receptor agonists in anaesthetic practice have alsobeen investigated. The sedative effect of alpha-2 agonists is regardedas good component of premedication. Another beneficial effect of alpha-2agonists in anaesthetic practice is their ability to potentiate theanaesthetic action of other agents and to reduce anaestheticrequirements of other drugs during surgery. Studies shows thatpremedication with 5 μg kg⁻¹ of oral clonidine administration reducedfentanyl requirements for induction and intubation by 45% in patientundergoing aortocoronary bypass surgery (Ghingnone, M, et al,Anesthesiology 1986, 64, 36).

This invention is directed to novel benzimidazole derivatives which areselective for cloned human alpha 2 receptors. This invention is alsorelated to uses of these compounds as analgesic, sedative andanaesthetic agents. In addition, this invention includes using suchcompounds for lowering intraocular pressure, and treatment of migraine,hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis,ischemia, spasticity, diarrhea, nasal decongestion. Furthermore thecompounds may be useful as cognition enhancers.

SUMMARY OF THE INVENTION

This invention provides compounds having the structure:

wherein each of R₁, R₂, R₃ and R₉ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; acyl, phenyl, substitutedphenyl, or heteroaryl; wherein each dashed line represents a single bondor a double bond with the proviso that if R₁ is present, R₃ is absentand there is a double bond between N at position 3 and C at position 2and a single bond between C at position 2 and N at position 1 and if R₃is present, R₁ is absent and there is a double bond between N atposition 1 and C at position 2 and a single bond between C at position 2and N at position 3; wherein each of R₄, R₅ and R₆ is independently H,F, Cl, Br, I; straight chain or branched, substituted or unsubstitutedC₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl;phenyl, substituted phenyl, heteroaryl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇,—CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, —(CH₂)_(n)NR₇COR₇, wherein n is an integer from 1 to4; and wherein each of R₇ and R₈ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; phenyl or substituted phenyl.

These compounds are selective for cloned human alpha 2 receptors and areuseful as analgesic, sedative or anaesthetic agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structure:

where each of R₁, R₂, R₃ and R₉ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; acyl, phenyl, substitutedphenyl, or heteroaryl; where each dashed line represents a single bondor a double bond with the proviso that if R₁ is present, R₃ is absentand there is a double bond between N at position 3 and C at position 2and a single bond between C at position 2 and N at position 1 and if R₃is present, R₁ is absent and there is a double bond between N atposition 1 and C at position 2 and a single bond between C at position 2and N at position 3; where each of R₄, R₅ and R₆ is independently H, F,Cl, Br, I; straight chain or branched, substituted or unsubstitutedC₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl;phenyl, substituted phenyl, heteroaryl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇,—CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, —(CH₂)_(n)NR₇COR₇, where n is an integer from 1 to 4;and where each of R₇ and R₈ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; phenyl or substituted phenyl.

The compound may have the following preferred structure:

where each of R₁, R₂, R₃, R₄ and R₆ is defined above.

In addition, the invention further describes compounds having thefollowing structures:

Acid salts of the compounds described above may be also be prepared. Theacid salts may be but are not limited to the following HCl, HBr, HI,H₂SO₄, CH₃COOH, CF₃COOH, HNO₃, CF₃SO₃H, CH₃SO₃H, C₄H₄O₄, HO₂CCH═CHCO₂H,HO₂CCH═CHCO₂H, HO₂CCH(OH)CH(OH)CO₂H.

The invention also describes a pharmaceutical composition comprising atherapeutically effective amount of the compounds described above and apharmaceutically acceptable carrier.

The invention further describes a method for treating an alpha-2adrenergic receptor associated disorder or alleviating pain in a subjectwhich comprises administering to the subject an amount of a compoundhaving the structure:

where each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ is defined above.

The invention describes a method for treating an alpha-2 adrenergicreceptor associated disorder or alleviating pain in a subject whichcomprises administering to the subject an amount of a compound havingthe structure:

where each of R₁, R₂, R₃, R₄ and R₆ is defined above.

The invention describes a method for alleviating pain in a subject whichcomprises administering to the subject an amount of a compound havingthe structure:

The method described above may be used to treat alpha-2 adrenergicreceptor associated disorders such as hypertension, rheumatoidarthritis, ischemia, spasticity, glaucoma, migraines, alcoholwithdrawal, drug addiction, diarrhea, or nasal congestion.

The compounds may be administered to a subject suffering from an alpha-2adrenergic receptor associated disorder. The effective quantity of thecompounds described above is from about 0.01 mg/dose to about 100mg/dose and preferably from about 0.1 mg/dose to about 20 mg/dose. Suchdose levels will depend upon the half-life of the compounds see forexample Goodman and Gilman's “The Pharmacological Basis ofTherapeutics,” Eighth Edition, 1990, Pergamon Press, pages 3-32.

Administration for the above compounds may be by any conventional routeof administration, including, but not limited to, intravenous,intramuscular, oral, ophthalmic, subcutaneous, intratumoral,intradermal, and parenteral.

The present invention also provides compounds useful for preparing apharmaceutical composition comprising any of the compounds disclosedherein and a pharmaceutically acceptable carrier. The composition maycontain between 0.1 mg and 500 mg of any of the compounds, and may beconstituted in any form suitable for the mode of administrationselected.

The compounds may be administered neat or with a pharmaceutical carrierto a patient in need thereof. The pharmaceutical carrier may be solid orliquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired.

The powders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously.

The compound may be prepared as a sterile solid composition which may bedissolved or suspended at the time of administration using sterilewater, saline, or other appropriate sterile injectable medium. Carriersare intended to include necessary and inert binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS General Methods

Four general synthetic methods were used to synthesize the compoundsdescribed herein. These methods are illustrated in Reaction Schemes 1-4.

The compounds herein have been prepared using synthetic sequences shownin Schemes 1-4. C-4 halogen substituted 5-aminobenzimidazoles wereobtained from commercially available 5-nitrobenzimidazole by thesequence of hydrogenation and halogenation. C-4 alkyl substitutedanalogs were prepared in a similar reaction sequence in which alkylgroup was incorporated using a Grignard reaction (Scheme 1). Reaction of5-aminobenzimidazole with 2-imidazoline-2-sulfonic acid (ISA) which wasobtained from 2-imidazolinethione (Gluchowski, C. U.S. Pat. No.5,130,441) provides access to 2-aminoimidazolines in high yield(45-95%). C-2 substituted 5-nitrobenzimidazoles were prepared bycondensation of 4-nitro-1,2-phenylenediamine with corresponding acids(Scheme 2). C-2 substituted 5-nitrobenzimidazoles were subjected to thesame reaction sequence as Scheme 1 to provide the desired final product.Reaction of alkyl halides with 5-nitrobenzimidazole in the presence ofNaH provided both N-1 and N-3 substituted benzimidazoles (Scheme 3). Thereaction mixtures were subjected to hydrogenation (H₂/Pd-C) to producethe corresponding amines, which were separated on column chromatography.Each amine was subjected to the reaction sequence described in Scheme 1to provide the final product.

Preparation of C-7 substituted benzimidazoles is illustrated in Scheme4. Halogenation of 2,4-dinitroaniline provided 6-halogen substitutedanilines, which were subjected to hydrogenation and condensation informic acid to provide 7-halosubstituted 5-aminobenzimidazoles. Theseintermediates were coupled to ISA to provide the desired products. C-7alkyl substituted benzimidazoles were prepared using a similar sequenceof reactions. Accordingly, 6-bromo-2,4-dinitroaniline was converted to6-alkyl or aryl substituted analogs by the Pd(II) catalyzed couplingreaction. Conversion of alkyl substituted anilines to benzimidazoles wascarried out in same reaction sequences described in Scheme 2.

EXAMPLE 1 5-(2-Imidazolin-2-ylamino) benzimidazole (#1)

5-Aminobenzimidazole. A solution of 5-nitrobenzimidazole (4.0 g, 25mmol) and 10% Pd/C (0.5 g) was stirred under H₂ for 12 h. The reactionmixture was filtered through Celite-assisted funnel and concentrated invacuo, yielding 3.2 g (25 mmol, >95%) of the desired product, which wascharacterized by NMR and subjected to following reactions withoutfurther purification.

2-Imidazoline-2-sulfonic acid (ISA) ISA was prepared according to theprocedure described in literature (Gluchowski, C. U.S. Pat. No.5,130,441, 1992). To a solution of 2-imidazolinethione (6.6 g, 65 mmol),sodium molybdate(IV) dihydrate (0.5 g, 2.1 mmol) and NaCl (1.5 g) in 150ml of distilled water was added 30% of H₂O (50 ml, 450 mmol) for 1 h at−10° C. The reaction mixture was stored at −20° C. for 12 h and thenreaction temperature was slowly warmed up to 25° C. The white crystalobtained was filtered and dried in vacuo to provide 2.8 g (21 mmol, 32%)of the acid. The compound was used in the examples noted below.

5-(2-Imidazolin-2-ylamino) benzimidazole. A solution of5-aminobenzimidazole (1.0 g, 7.5 mmol) and ISA (2.5 g, 18.8 mmol) in 10ml of isobutanol was stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo to yield an oily residue which was subjectedto silica gel column chromatography (20% NH, sat'd MeOH/EtOAc) toproduce 0.77 g (3.8 mmol, 53%) of the product. The product obtained wasconverted to the fumarate salt and recrystallized from MeOH to afford0.21 g (27%) of the product as a white solid: mp 196-198° C.; Anal.Calc. for C₁₀H₁₁N₅.1.0C₄H₄O₄.1.3H₂O requires C, 49.62; H, 4.65; N,20.67. Found: C, 49.65; H, 5.73; N, 20.53.

EXAMPLE 2 4-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#2)

4-Bromo-5-aminobenzimidazole. To a solution of 5-aminobenzimidazole (0.3g, 2.3 mmol) in 30 ml of AcOH was added bromine, (0.055 ml, 1.1 mmol) ina portion and resulting reaction mixture was stirred for 0.5 h at 25° C.Reaction mixture was concentrated in vacuo, yielding a dark brown solidwhich was subjected to silica gel column chromatography (NH₃ saturated10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.

4-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of4-bromo-5-aminobenzimidazole (0.22 g, 0.97 mmol) and ISA (0.34 g, 2.5mmol) in 5 ml of isobutanol was stirred at reflux for 12 h. Reactionmixture was concentrated in vacuo and subjected to silica gel columnchromatography (NH₃ saturated 20% MeOH/EtOAc) to yield 0.23 g (0.83mmol, 84%) of the product. The product obtained was converted to thefumarate salt and recrystallized from MeOH to afford 0.12 g (30%) of theproduct as a white solid: mp 199-202° C. Anal. Calc. forC₁₀H₁₀N₅Br.1.0C₄H₄O₄.0.7H₂O requires C, 41.13; H, 3.80; N, 17.13. Found;C, 41.60; H, 3.81; N, 16.97.

EXAMPLE 3 4-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole (#3)

4-Chloro-5-aminobenzimidazole. To a solution of 5-aminobenzimidazole(1.0 g, 7.5 mmol) in 20 ml of AcOH was added Cl₂ saturated AcOH solutionuntil it produced a precipitation. The reaction mixture was concentratedin vacuo, yielding a dark residue which was subjected to columnchromatography (NH₃ sat'd 30% MeOH/EtOAc) to yield 120 mg (0.72 mmol) of4-chloro-5-aminobenzimidazole.

4-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole. The amine (120 mg, 0.72 mmol) was mixed with ISA (250 mg, 1.8 mmol), and resulting mixturewas stirred for 12 h at reflux. Column chromatographic separation (NH₃sat'd 30% MeOH/EtOAc) of the reaction mixture yielded 140 mg (0.62 mmol,87%) of the desired product. The product obtained was converted to thefumarate salt and recrystallized from EtOH to afford 50 mg (20%) of theproduct as a white solid: MP 207-208° C.; Anal. Calc. forC₁₀H₁₀N₅Cl.1.0C₄H₄O₄.0.6H₂O requires C, 46.38; H 4.23; N, 19.32. Found:C, 46-32; H, 4.23; N, 19.47.

EXAMPLE 4 4-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#4)

4-Methyl-5-aminobenzimidazole. A solution of4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol), tetramethyltin (330mg, 2.4 mmol) and bis (triphenylphosphine) palladium (11) chloride (20mg) in 5 ml of anhydrous DMF was placed in sealed tube and stirred for12 h at 145° C. The reaction mixture was concentrated in vacuo, yieldingan oily residue which was subjected to column chromatographic separation(NH, sat'd 10% MeOH/EtOAc) to yield 140 mg (0.83 mmol, >95%) of4-methyl-5-aminobenzimidazole.

4-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine obtained wasplaced in flask with ISA (0.38 g, 2.5 mmol) and 5 ml of isobutanol, andresulting mixture was stirred at reflux for 12 h. Column chromatographicseparation (NH, sat'd 10% MeOH/EtOAc) of the reaction mixture provided0.15 g (0.71 mmol, 84%) of the desired product. The product obtained wasconverted to the fumarate salt and recrystallized from MeOH to afford 92mg (25%) of the product as a white solid: mp 155-157° C. Anal. Calc. forC₁₁H₁₃N₅.1.5C₄H₄O₄.0.5H₂O requires C, 52.08; H, 4.96; N, 17.86. Found:C, 52.08; H, 4.97; N, 17.80.

EXAMPLE 5 4-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole (#5)

4-Iodo-5-aminobenzimidazole. To a solution of 5-aminobenzimidazole (0.6g, 4.5 mmol) and Hg (OAc)₂ (1.72 g, 5.5 mmol) in 20 ml of AcOH was addeda solution of I₂ until solution produces a precipitation. The reactionmixture was concentrated in vacuo, yielding an oily residue which wassubjected to column chromatographic separation (NH₃ sat'd 10%MeOH/EtOAc) to produce 0.30 (1.2 mmol, 26%) g of4-iodo-5-aminobenzimidazole.

4-Iodo-5-(2-imidazolin-2-ylmino)benzimidazole. A solution of the amine(0.30 g, 1.1 mmol) and ISA (0.62 g, 4.4 mmol) was stirred at reflux for12 h. Column chromatographic separation of the reaction mixture (NH₃sat'd 20% MeOH/EtOAc) provided 0.12 g (0.34 mmol, 31%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from EtOH to afford 0.12 g (20%) of the product as awhite solid: mp 256° C. Anal. Calc. for C₁₀H₁₀N₅I.2.0C₄H₄O₄. 1.0H₂Orequires C, 37.45; H, 3.49; N, 12.13. Found: C, 37.52; H, 3.51; N,12.62.

EXAMPLE 6 4-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole (#6)

4-Ethyl-5-aminobenzimidazole. To a solution of 5-nitrobenzimidazole (2.8g, 17 mmol) in THF was added 16 ml of EtMgBr solution (48 mmol) andreaction mixture was stirred for 2 h at −15° C. A solution oftetrachloro-1,4-benzoquinone (8.8 g, 36 mmol) in THF was added dropwiseinto reaction mixture, which was allowed to warm up to 25° C. over 1 h.Silica gel (20 g) was added into reaction mixture and solvent wasremoved in vacuo to provide a brown silica gel powder which wassubjected to column chromatography (EtOAc, neat) to provide 1.7 g (8.9mmol, 52%) of 4-ethyl-5-nitrobenzimidazole, which was subsequentlysubjected to hydrogenation (H₂, Pd/C) to yield 1.32 g (8.2 mmol) of4-ethyl-5-aminobenzimidazole.

4-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of the amine(0.71 g, 4.3 mmol) and ISA (0.75 g, 5.6 mmol) in 10 ml of isobutanol wasstirred at reflux for 12 h. The reaction mixture was concentrated invacuo, yielding an oil, which was subjected to column chromatography(NH₃ sat'd 3 0% EtOH/EtOAc) to yield 0. 26 g (1.2 mmol, 28%) of thedesired product. The product obtained was converted to the fumarate saltand recrystallized from MeOH to afford 0.22 g (16%) of the product as alight brown solid: mp 238-239° C. Anal. Calc. for C₁₂H₁₅N₅.1.0C₄H₄O₄requires C, 55.60; H, 5.55; N, 20.28. Found: C, 54.63; H, 5.70; N,19.46.

EXAMPLE 7 4-n-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole (#7)

4-n-Propyl-5-aminobenzimidazole. To a solution of 5-nitrobenzimidazole(2.3 g, 14 mmol) was added 14 ml of n-PrMgBr solution (42 mmol) andreaction mixture was stirred for 2 h at −15° C. The reaction wasquenched by adding a solution of tetrachloro-1,4-benzoquinone (4 g, 16mmol) in 10 ml of THF. The reaction mixture was concentrated in vacuo toprovide an oil, which was subjected to column chromatographic separation(EtOAc, neat) to provide 1.4 g (7.2 mmol, 52%) of4-n-propyl-5-nitrobenzimidazole, which was converted to thecorresponding amine (1.2 g, >95%) by hydrogenation (H₂, Pd/C).

4-n-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine (1.2 g, 14mmol) was stirred with ISA (1.5 g, 11.2 mmol) at reflux for 12 h.Concentration of reaction mixture produced an oily residue, which wassubjected to column chromatographic separation (NH₃ sat'd 30%MeOH/EtOAc) to provide 0.63 g (2.6 mmol, 37%) of the Desired product.The product obtained was converted to the fumarate salt andrecrystallized from EtOH to afford 0.45 g (16%) of the product as alight brown solid: mp 229-230° C.

EXAMPLE 8 4-n-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole (#8)

4-n-Butyl-5-aminobenzimidazole. To a solution of 5-nitrobenzimidazole(0.41 g, 2.5 mmol) was added a solution of n-BuLi (7.5 mmol) andreaction mixture was stirred for 1 h at 0° C. The reaction mixture wasquenched by adding a few drops of H₂O and concentrated in vacuo-yieldingan oil which was subjected to silica gel column chromatography (5%MeOH/ETOAC) to provide 0.13 g of 4-n-butyl-5-nitrobenzimidazole and 0.19g of 4-n-butyl-5-aminobenzimidazole. The nitrobenzimidazole wasconverted to the amine in hydrogenation (H₂./Pd-C) to provide 0.28 g(1.5 mmol, 60%) of the desired product.

4-n-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole. The amine (0-28 g,1.5 mmol) was refluxed with ISA (0.50 g, 3.7 mmol) in isobutanol for 12h. Column chromatographic separation of reaction mixture (NH₃ sat'd 20%MeOH/EtOAc) provided 0.21 g (0.81 mmol, 54%) of the product. The productobtained was converted to the fumarate salt and recrystallized fromisopropanol to afford 0.38 g (49%) of the product as a foamy solid: mp96° C. Anal. Calc. For C₁₄H₁₉N₅. 2.0C₄H₄O₄. requires C, 55.68; H, 5.86;N, 16.23. Found: C, 55.98; H, 5.68; N, 16.49.

EXAMPLE 9 1-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#9)

1- and 3-Methyl-5-aminobenzimidazole. A solution of 5-nitrobenzimidazole(3.0 g, 18.4 mmol) in 100 ml of THF was stirred with NaH (2.7 g, 36.8mmol) for 0.5 h at 25° C. To the solution was added methyl iodide (2.0ml, 20.3 mmol) and resulting mixture was stirred for 12 h. The reactionmixture was concentrated in vacuo to provide an oil, which was dissolvedin 200 ml of MeOH and stirred with 0.3 g of 10% Pd/C under H₂ for 12 h.The reaction mixture was filtered and concentrated in vacuo, yielding adark oily residue which was subjected to column chromatography (3%MeOH/CHCl,) to provide 0.69 g (3.9 mmol, 21%) of1-methyl-5-aminobenzimidazole and 0.36 g (2.0 mmol, 11%) of3-methyl-5-aminobenzimidazole.

1-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of1-methyl-5-aminobenzimidazole (0.15 g, 1.1 mmol) and ISA (0.30 g, 2.2mmol) in 3 ml of isobutanol was stirred at reflux for 12 h. The reactionmixture was concentrated in vacuo, yielding an oily residue which waspurified on silica gel column chromatography (NH₃ sat'd 20%isopropanol/EtOAc) to yield 0.12 g (0.56 mmol, 51%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.11 g (30%) of the product asa white-crystal: mp 210-211° C.; Anal. Calc. for C₁₁H₁₃N₅.1.0C₄H₄O₄.0.3H₂O requires C, 35.36; H, 5.28; N,20.74. Found: C, 53.67; H, 5.13; N,20.70.

EXAMPLE 10 1-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#10)

1-Methyl-4-bromo-5-aminobenzimidazole. To a solution of1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10 ml of AcOH wasadded Br₂ (0.12 ml). The reaction mixture was stirred for 1 h at 25° C.and concentrated in vacuo, yielding an oil which was subjected to columnchromatography (NH₃ sat'd 3% MeOH/CHCl,) to yield 0.27 g (1.2 mmol, 50%)of the desired product.

1-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Isobutanolicsolution of the amine (0.27 g, 1.2 mmol) and ISA (0.6 g, 4.5 mmol, wasstirred at reflux for 12 h. The reaction mixture was concentrated invacuo, yielding An oily residue which was subjected to columnchromatography (NH₃ sat'd 20% MeOH/EtOAc) to yield 0.33 g (1.1 mmol,92%) of the expected product. The product obtained was recrystallizedfrom EtOH to afford 0.21 g (64%) of the product as a white crystal: mp237-238° C.; Anal. Calc. for C₁₁H₁₂N₅Br.1.75H₂O requires C, 40.57; H,4.80; N, 21.50. Found: C, 40.98, H, 4.81; N, 21.41.

EXAMPLE 11 3-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#11)

A solution of 3-methyl-5-aminobenzimidazole (0.20 g, 1.5, mmol) and ISA(0 .45 g, 3.4 mmol) was stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo and purified on column chromatography (NH,sat'd 20% MeOH/EtOAc) to yield 0.19 g (0.88 mmol, 59%) of the product.The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 0.31 g (46%) of the product as awhite crystal: mp 202-204° C. Anal. Calc. for C₁₁H₁₃N₅. 2.0C₄H₄O₄requires C, 51.01; H, 4.73; N, 15.65. Found: C, 51.65; H, 4.76; N,15.78.

EXAMPLE 12 3-Methyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole (#12)

3-Methyl-4-bromo-5-aminobenzimidazole. To a solution of3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10 ml of AcOH wasadded BR₂ (0.10 ml). The reaction mixture was stirred for 1 h at 25° C.and concentrated in vacuo, yielding an oil which was subjected to columnchromatography (NH₃ sat'd 3% MeOH/CHCl,) to yield 0.14 g (0.62 mmol,35%) of the desired product.

3-Methyl-4-bromo-5-(imidazolin-2-ylamino) benzimidazole. A solution of3-methyl-4-bromo-5-aminobenzimidazole (0.31 g, 1.4 mmol) and ISA (0.6 g,4.5 mmol) in 10 ml of isobutanol was stirred at reflux for 12 h. Oilyresidue obtained was subjected to column chromatography (NH₃ sat'd 20%isopropanol/EtOAc) to yield 0.39 g (1.3 mmol, 93%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 0.50 g (68%) of the product as awhite solid: mp 209-210° C. Anal. Calc. For C₁₁H₁₂N₅Br.2.0C₄H₄O₄.requires C, 43.36; H, 3.83; N, 13.31 Found: C, 43.66; H, 3.84; N, 13.10.

EXAMPLE 13 1-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole (#13)

1- and 3-Propyl-5-aminobenzimidazole. A solution of 5-nitrobenzimidazole(3.6 g, 23 mmol) in 100 ml of THF was stirred with NaH (1.5 g, 33 mmol)for 0.5 h at 25° C. To the solution was added allyl bromide (4.8 ml, 57mmol) and resulting mixture was stirred for 12 h. The reaction mixture,was concentrated in vacuo to provide an oil, which was subjected tocolumn chromatography to yield 4.0 g (19.7 mmol, 89%) of a mixture of 1-and 3-allyl-5-nitrobenzimidazole. The nitrobenzimidazole mixture wasstirred in 100 ml of MeOH for 12 under H₂ in the presence of 10% Pd/C.The reaction mixture was filtered and concentrated in vacuo to provideoily residue which was subjected to column chromatography (50%Hexane/EtOAc) to provide 1.2 g (7.0 mmol) of1-propyl-5-aminobenzimidazole and 1.1 g (6.4 mmol) of3-propyl-5-aminobenzimidazole.

1-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. Reaction of1-propyl-5-aminobenzimidazole (1.2 g, 7.0 mmol) and ISA (2.2 g, 16 mmol)provided 1.6 g (6.6 mmol,

94%) of the expected product after column chromatographic separation.The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 2.1 g (76%) of the product as a lightbrown solid: mp 206-207° C.; Anal. Calc. for C₁₃H₁₇N₅.1.5C₄H₄O₄ requiresC, 54.67; H, 5.55; N, 16.98. Found: C, 54.60; H, 5.49; N, 17.16.

EXAMPLE 14 1-Propyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole (#14)

1-Propyl-4-bromo-5-aminobenzimidazole. To a solution of1-propyl-5-aminobenzimidazole (1.2 g, 7.1 mmol) in 10 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5%) NH₃ sat'd MeOH/CH₂Cl₂)to provide 0.83 g (3.4 mmol, 48%) of the product.

1-Propyl-4-bromo-5-(imidazolin-2-ylamino)benzimidazole. A reaction ofthe amine (0.83 g, 3.4 mmol) and ISA (1.3 g, 9.7 mmol) produced 0.44 g(1.3 mmol, 38%) of the product after chromatographic separation. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.32 g (25%) of the product as a light brownsolid: mp 206-207° C. Anal. Calc. for C₁₃H₁₆N₅Br.0.5C₄H₄O₄.0.5H₂Orequires C, 46.29; H, 4.92; N, 17.99. Found: C, 46.66; H, 4.86; N,17.60.

EXAMPLE 15 3-Propyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#15)

A reaction of 3-propyl-5-aminobenzimidazole (1.0 g, 5.8 mmol) and ISA(1.9 g, 14 mmol) provided 1.3 g (5.0 mmol, 87%) of product after columnchromatography. The product obtained was converted to the fumarate saltand recrystallized from isopropanol to afford 0.32 g (25%) of theproduct as a white solid: mp 198-199° C. Anal. Calc. forC₁₃H₁₇N₅.1.0C₄H₄O₄ requires C, 56.82; H, 5.89; N, 19.49. Found: C,57.12; H, 5.91; N, 19.61.

EXAMPLE 16 3-Propyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#16)

3-Propyl-4-bromo-5-aminobenzimidazole. To a solution of3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 0.40 g (1.6 mmol, 37%) of the product.

3-Propyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction of3-propyl-4-bromo-5-aminobenzimidazole (0.40 g, 1.6 mmol) and ISA (0.7 g,5.2 mmol) provided 0.32 g (1.3 mmol, 81%) of product after columnchromatography. The product obtained was converted to the fumarate saltand-recrystallized from isopropanol to afford 0.30 g (58%) of theproduct as a white solid: mp 179-181° C. Anal. Calc. forC₁₃H₁₆N₅Br.1.0C₄H₄O₄ requires C, 46.59; H, 4,60; N, 15.98. Found: C,46.36; H, 4.49; N, 15.81.

EXAMPLE 17 1-Isopropyl-5-(2-imidazolin-2-ylamino)benzimidazole (#17)

1- and 3-Isopropyl-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (4.8 g, 29 mmol) and isopropyl bromide (3.7 ml) ina procedure described in Example 9 produces 5.1 g (23 mmol, 8%) of amixture of 1- and 3-isopropyl-5-nitrobenzimidazole, which was convertedto the corresponding amines in hydrogenation (H₂/Pd-C). The aminemixture was subjected to column chromatography (10% i-PrOH/CH₂Cl₂) toprovide 1.5 g (7.9 mmol, 27%) of 1-isopropyl-5-aminobenzimidazole and2.4 g (12.6 mmol, 44%) of 3-isopropyl-5-aminobenzimidazole.

1-Isopropyl-5-(2-imidazolin-2-ylamino) benzimidazole. Reaction of1-isopropyl-5-aminobenzimidazole (0.41 g, 2.3 mmol) and ISA (0.70 g, 5.2mmol) provided 0.37 g (1.5 mmol, 66%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from isopropanol to afford 0.27 g(24%) of the product as a light brown solid: mp 185-186° C. Anal. Calc.for C₁₃H₁₇N₅.2.0C₄H₄O₄ requires C, 52.83; H, 5.70; N, 14.67. Found: C,53.32; H, 5.63; N, 14.97.

EXAMPLE 18 1-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#18)

1-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of1-isopropyl-5-aminobenzimidazole (2.4 g, 14 mmol) in 20 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 1.2 g (4.5 mmol, 35%) of the product.

1-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof the amine (0.86 g, 3.4 mmol) and ISA (0.90 g, 6.7 mmol) produced 0.67g (2.1 mmol, 61%) of the product after chromatographic separation. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.55 g (37%) of the product as a light brownsolid: mp 187-188° C.; Anal. Calc. for C₁₃H₁₆N₅Br.1.0C₄H₄O₄ requires C,46.59; H, 4.60; N, 15.98. Found: C, 46.35; H, 4.49; N, 15.82.

EXAMPLE 19 1-Isopropyl-4-Iodo-5-(2-imidazol in-2-ylamino)benzimidazole(#19)

1-Isopropyl-4-iodo-5-aminobenzimidazole. To a solution of1-isopropyl-B-aminobenzimidazole (0.70 g, 3.7 mmol) and Hg(OAc)₂ (2.1 g,5.6 mmol) in 10 ml of AcOH was added solution of I₂ in AcOH until itproduces a precipitation. The reaction mixture was concentrated in vacuoto provide a brown solid which was subjected to column chromatography(5% NH₃ sat'd MeOH/CH₂Cl₂) to provide 0.40 g (1.3 mmol, 35%) of theproduct.

1-Isopropyl-4-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof the amine (0.40 g, 1.3 mmol) and ISA (0.5 g, 3.7 mmol) produced 0.18g (0.48 mmol, 37%) of the product after chromatographic separation. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.22 g (35%) of the product as a white solid:mp 208-209° C. Anal. Calc. for C₁₃H₁₆N₅I.1.0C₄H₄O₄ requires C, 42.08; H,4.15; N, 14.43. Found: C, 41.86; H, 4.06; N, 14.17.

EXAMPLE 20 3-Isopropyl-5-(2-imidazolin-2-ylamino)benzimidazole. (#20)

A reaction of 3-isopropyl-5-aminobenzimidazole (1.0 g, 5.8 mmol) and ISA(1.5 g, 11 mmol) yielded 0.90 g (3.8 mmol, 65%) of product after columnchromatography. The product obtained was converted to the fumarate saltand recrystallized from isopropanol to afford 0.32 g (25%) of theproduct as a light brown solid: mp 206-207° C.; Anal. Calc. forC₁₃H_(l7)N₅0.5C₄H₄O₄ requires C, 54.67; H, 5.55; N, 16.78. Found: C,53.33; H, 5.50; N, 16.30.

EXAMPLE 21 3-Isopropyl-4-bromo-5-(2-imidazolin-2ylamino)benzimidazole(#21)

-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of3-isopropyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 1.1 g (4.0 mmol, 47%) of the product.

3-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino) benzimidazole. A reactionof 3-isopropyl-4-bromo-5-aminobenzimidazole (1.1 g, 4.0 mmol) and ISA(1.2 g, 9.0 mmol) provided 0.60 g (1.9 mmol, 43%) of product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from EtOH to afford 0.52 g (28%) of theproduct as a white crystal: mp 210-212° C. Anal. Calc. forC₁₃H₁₆N₅Br.1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N, 15.98. Found: C,46.60; H, 4.49; N, 15.74.

EXAMPLE 22 1-Isobutyl-5-(2-imidazolin-2-ylamino)benzimidazole (#22)

1- and 3-Isobutyl-5-aminobenzimidazole A reaction of5-nitrobenzimidazole (4.8 g, 29 mmol) and isobutyl bromide (7.7 ml, 72mmol) in a procedure described in Example 9 produces 5.3 g (24 mmol,83%) of a mixture of 1- and 3-isopropyl-5-nitrobenzimidazole, which wasconverted to the corresponding amines in hydrogenation (H₂/Pd-C). Theamine mixture was subjected to column chromatography (10% i-PrOH/CH₂Cl₂)to provide 1.8 g (9.4 mmol, 32%) of 1-isobutyl-5-aminobenzimidazole and2.7 g (14 mmol, 49%) of 3-Isobutyl-5-aminobenzimidazole.

1-Isobutyl-5-(2-imidazolin-2-ylamino)benzimidazole. Reaction of1-isobutyl-5-aminobenzimidazole (0.29 g, 1.2 mmol) and ISA (0.6 g, 4.5mmol) provided 0.37 g (1.2 mmol, >95%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from isopropanol to afford 0.41 g(70%) of the product as a white solid: mp 185-186° C. Anal. Calc. forC₁₄H₁₉N₅.2.0C₄H₄O₄ requires C, 53.,98; H, 5.56; N, 14.31. Found: C,53.85 H, 5.69; N, 14.22.

EXAMPLE 23 1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#23)

1-Isobutyl-4-bromo-5-aminobenzimidazole. To a solution of1-isobutyl-5-aminobenzimidazole (2.4 g, 13 mmol) in 20 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5%) NH, sat'd MeOH/CH₂Cl₂)to provide 1.2 g (4.5 mmol, 35%) of the product.

1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof bromoamine (0.30 g, 1.1 mmol) and ISA (0.9 g, 6.7 mmol) produced 0.28g (0.81 mmol, 73%) of the product after chromatographic separation. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.28 g (56%) of the product as a white solid:mp 226-227° C.

EXAMPLE 24 3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino) benzimidazole(#24)

3-Isobutyl-4-bromo-5-aminobenzimidazole. To a solution of3-Isobutyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 1.0 g (3.7 mmol, 29%) of the product.

3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino) benzimidazole-A reactionof 3-isobutyl-4-bromo-5-aminobenzimidazole (0.30 g, 1.1 mmol) and ISA(0.70 g, 5.2 mmol) provided 0.20 g (0.56 mmol, 51%) of the product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.22 g (45%)of the product as a white solid: mp 187-188° C. Anal. Calc. forC₁₄H₁₈N₅Br.1.0C₄H₄O₄ requires C, 47.80; H, 4.90; N, 15.48. Found: C,47.57; H, 4.61; N, 15.38.

EXAMPLE 25 1-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole (#25)

1- and 3-Cyclopentyl-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclopentyl bromide (3.8 ml,38 mmol) in a procedure described in Example 9 produces 2.6 g (11 mmol,59%) of a mixture of 1- and 3-cyclopentyl-5-nitrobenzimidazole, whichwas converted to the corresponding amines in hydrogenation (H₂/Pd-C).The amine mixture was subjected to column chromatography (10%i-PrOH/CH₂Cl₂) to provide 1.0 g (5.0 mmol, 45%) of1-cyclopentyl-5-aminobenzimidazole and 1.1 g (5.4 mmol, 50%) of3-cyclopentyl-5-aminobenzimidazole.

1-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction of1-cyclopentyl-5-aminobenzimidazole (0.66 g, 3.3 mmol) and ISA (1.3 g,9.7 mmol) provided 0.91 g (2.7 mmol, 81%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from isopropanol to afford 1.1 g(77%) of the product as a white crystal: mp 214-215° C.; Anal. Calc. ForC₁₅H₁₉N₅.1.5C₄H₄O₄ requires C, 56.88; H, 5.68; N, 15.79. Found: C,56.69; H, 5.54; N, 16.02.

EXAMPLE 26 1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#26)

1-Cylcopentyl-4-bromo-5-aminobenzimidazole. To a solution of1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of AcOHwas added solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 0.54 g (1.9 mmol, 35%) of the product.

1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of the amine (0.54 g, 1.9 mmol) and ISA (0.74 g, 5.5 mmol)produced 0.45 g (1.3 mmol, 67%) of the product after chromatographicseparation. The product obtained was converted to the fumarate saltrecrystallized from isopropanol to afford 0.32 g (19%) of the product asa light brown solid: mp 180-182° C.; Anal. Calc. forC₁₅H₁₈N₅Br.1.5C₄H₄O₄ requires C, 48.29; H, 4.63; N, 13.41. Found: C,48.56; H, 4.54; N, 13.23.

EXAMPLE 27 3-Cyclopentyl-5-(2-imidazolin-2-ylamino)benzimidazole (#27).

A reaction of 3-cyclopentyl-5-aminobenzimidazole (0.41 g, 2.0 mmol) andISA (0.68 g, 5.1 mmol) yielded 0.34 g (1.2 mmol, 62%) of product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.28 g (31%)of the product as a white solid: mp 158-159° C.; Anal. Calc. forC₁₅H₁₉N₅.1.0C₄H₄O₄ requires C, 56.88; H, 5.68; N, 15.79. Found: C,55.69; H, 5.62; N, 15.73.

EXAMPLE 28 3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#28)

3-Cyclopentyl-4-bromo-5-aminobenzimidazole. To a solution of3-cyclopentyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 20 ml of AcOHwas added solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 0.70 g (2.5 mmol, 50%) of the product.

3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of 3-cyclopentyl-4-bromo-5-aminobenzimidazole (0.70 g, 2.5mmol) and ISA (0.94 g, 0.70 mmol) provided 0.26 g (0.78 mmol, 31%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 0.31g (27%) of the product as a white solid: mp 208-210° C.; Anal. Calc. forC₁₅H₁₈N₅Br.1.0C₄H₄O₄ requires C, 49.15; H, 4.78; N, 15.08. Found: C,49.46; H, 4.88; N, 15.38.

EXAMPLE 29 1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)benzimidazole(#29)

1- and 3-Cyclohexylmethyl-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclohexylmethyl bromide (6.7ml, 47 mmol) in a procedure described in Example 9 produces 5.0 g (19mmol, 100%) of a mixture of 1- and3-cyclohexylmethyl-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% hexane/EtOAc) to provide 2.0g (8.7 mmol, 45%) of 1-cyclohexylmethyl-5-aminobenzimidazole and 2.5 g(11 mmol, 54%) of 3-cyclohexylmethyl-5-aminobenzimidazole.

1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof 1-cyclohexylmethyl-5-aminobenzimidazole (2.2 g, 9.6 mmol) and ISA(3.6 g) provided 1.8 g (8.1 mmol, 84%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from isopropanol to afford 1.9 g(4.6 mmol, 48%) of the product as a white solid: mp 222-223° C.; Anal.Calc. For C₁₇H₂₃N₅.1.0C₄H₄O₄ requires C, 61.00; H, 6.58; N, 16.94.Found: C, 61.48; H, 6.41; N, 16.36.

EXAMPLE 301-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#30)

1-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole. To a solution of1-cyclohexymethyl-5-aminobenzimidazole (2.5 g, 11 mmol) in 20 ml of AcOHwas added solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂)to provide 1.37 g (4.3 mmol, 40%) of the product.

1-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of the amine (1.4 g, 4.4 mmol) and ISA (1.8 g, 13 mmol)produced 1.6 g (4.1 mmol, 94%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 1.8 g (83%) of the product asa white solid: mp 193-195° C.; Anal. Calc. for C₁₇H₂₂N₂Br. 1.0C₄H₄O₄requires C, 51.23; H, 5.32; N, 14.22. Found: C, 50.21; H, 5.17; N,14.29.

EXAMPLE 313-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#31)

3-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole. To a solution of3-cyclohexylmethyl-5-aminobenzimidazole (2.0 g, 8.7 mmol) in 40 ml ofAcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CHCl₃) to provide 1.2 g (3.8 mmol, 40%) of the product.

3-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of 3-cyclohexylmethyl-4-bromo-5-aminobenzimidazole (1.2 g, 3.9mmol) and ISA (1.5 g, 11 mmol) provided 0.85 g (2.3 mmol, 58%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 1.1 g(51%) of the product as a white solid: mp 153-155° C.; Anal. Calc. forC₁₇H₂₂N₅Br.1.5C₄H₄O₄.0.5H₂O requires C, 49.38; H, 5.22; N, 12.58. Found:C, 49.22; H, 5.07; N, 12.19.

EXAMPLE 32 1-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole (#32)

1- and 3-Benzyl-5-aminobenzimidazole. A reaction of 5-nitrobenzimidazole(3.0 g, 18 mmol) and benzyl bromide (4.4 ml, 37 mmol) in a proceduredescribed in Example 9 produces 3.2 g (13 mmol, 71%) of a mixture of 1-and 3-benzyl-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% Hexane/EtOAc) to provide 1.6g (7.2 mmol, 55%) of 1-benzyl-5-aminobenzimidazole and 1.2 g (5.3 mmol,41%) of 3benzyl-5-aminobenzimidazole.

1-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction of1-benzyl-5-aminobenzimidazole (0.35 g, 1.2 mmol) and ISA (0.42 g, 3.1mmol) provided 0.17 g (0.46 mmol, 38%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from isopropanol to afford 0.11 g(20%) of the product as a white solid: mp 174-175° C.; Anal. Calc. ForC₁₇H₁₇N₅.1.5C₄H₄O₄ requires C, 59.35; H, 4.98; N, 45.05. Found: C,59.40; H, 4.81; N, 14.99.

EXAMPLE 33 1-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#33)

1-Benzyl-4-bromo-5-aminobenzimidazole. To a solution of1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitate. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CHCl₃)to provide 0.90 g (2.5 mmol, 60%) of the product.

1-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction ofbromoamine (0.90 g, 3.0 mmol) and ISA (1.2 g, 8.9 mmol) produced 0.85 g(2.3 mmol, 77%) of the product after chromatographic separation. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 1.1 g (70%) of the product as a white solid:mp 197-198° C.; Anal. Calc. for C₁₇H₁₆N₅Br.1.5C₄H₄O₄ requires C, 50.75;H, 4.07; N, 12.87. Found: C, 50.91; H, 3.87; N, 12.77.

EXAMPLE 34 3-Benzyl-5-(2-imidazolin-2-ylamino)benzimidazole (#34).

A reaction of 3-benzyl-5-aminobenzimidazole (0.34 g, 1.6 mmol) and ISA(0.68 g, 5.1 mmol) yielded 0.43 g (1.3 mmol, 76%), of product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.32 g (41%)of the product as a white solid: mp 174-175° C.; Anal. Calc. forC₁₇H₁₇N₅.1.5C₄H₄O₄ requires C, 59.35; H, 4.98; N, 15.05. Found: C,58.88; H, 5.19; N, 15.25.

EXAMPLE 35 3-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#35)

3-Benzyl-4-bromo-5-aminobenzimidazole. To a solution of3-benzyl-5-aminobenzimidazole (0.88 g, 3.9 mmol) in 20 ml of AcOH wasadded solution of Br₂ in AcOH until it produces a precipitation. Thereaction mixture was concentrated in vacuo to provide a brown solidwhich was subjected to column chromatography (5% NH₃ sat'd MeOH/CHCl₃)to provide 0.35 g (1.2 mmol, 29%) of the product.

3-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reaction of3-benzyl-4-bromo-5-aminobenzimidazole (0.35 g, 1.2 mmol) and ISA (0.43g, 3.2 mmol) provided 0.17 g (0.46 mmol, 38%) of the product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from MeOH to afford 0.12 g (21%) of theproduct as a white solid: mp 203-205° C.; Anal. Calc. forC₁₇H₁₆N₅Br.1.0C₄H₄O₄ requires C, 51.87; H, 4.64; N, 14.39. Found: C,52.60; H, 4.73; N, 14.39.

EXAMPLE 361-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#36)

1-(4-Methoxybenzyl)-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (4.3 g, 27 mmol) and 4-methoxybenzyl chloride (4.3ml, 30 mmol) in a procedure described in Example 9 produces 5.6 g (19mmol, 73%) of a mixture of 1- and3-(4-methoxybenzyl)-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% i-PrOH/CH₂Cl₂) to provide2.1 g (8.2 mmol, 43%) of 1-(4-methoxybenzyl)-5-aminobenzimidazole and2.4 g (9.2 mmol, 48%) of 3-(4-methoxybenzyl)-5-aminobenzimidazole.

1-(4-Methoxybenzyl)-4-bromo-5-aminobenzimidazole. To a solution of1-(4-methoxybenzyl)-5-aminobenzimidazole (0.80 g, 2.2 mmol) in 20 ml ofAcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CHCl₃) to provide 0.90 g (2.1 mmol, 95%) of the product.

1-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of the bromoamine (0.90 g, 2.1 mmol) and ISA (1.3 g, 9.7 mmol)provided 1.0 g (2.0 mmol, 96%) of the product after columnchromatography.

EXAMPLE 371-(3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#37)

1-(3-Methoxybenzyl)-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (2.5 g, 15 mmol) and 3-methoxybenzyl chloride (2.6ml, 17 mmol) in a procedure described in Example 9 produces 1.0 g (3.1mmol, 26%) of a mixture of 1- and3-(3-methoxybenzyl)-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% isopropanol/CH₂Cl₂) toprovide 0.32 g (1.1 mmol, 36%) of3-(3-methoxybenzyl)-5-aminobenzimidazole and 0.37 g (1.3 mmol, 41%) of1-(3-methoxybenzyl)-5-aminobenzimidazole.

1-(3-Methoxybenzyl)-4-bromo-5-aminobenzimidazole. To a solution of1-(3-methoxybenzyl)-5-aminobenzimidazole (0.37 g, 1.3 mmol) in 10 ml ofAcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dIsopropanol/CHCl₃) to provide 0.31 g (1.0 mmol, 66%) of the product.

1-(3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of the bromoamine (0.31 g, 0.84 mmol) and ISA (0.52 g, 3.9mmol) provided 0.37 g (>95%) of product after column chromatography. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.36 g (83%) of the product as a whitecrystal: mp 177-178° C.; Anal. Calc. for C₁₈H₁₈N₅BrO.1.0C₄H₄O₄.H₂Orequires C, 48.63; H, 4.64; N, 12.89. Found: C, 48.06; H, 4.51; N,12.77.

EXAMPLE 381-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#38)

1- and 3-(2-Hydroxyethyl)-4-bromo-5-aminobenzimidazole. A reaction of5-nitrobenzimidazole (3.3 g, 20 mmol) and 2-hydroxyethyl bromide (2.2ml, 31 mmol) in a procedure described in Example 9 produces a mixture of1- and 3-(2-hydroxyethyl)-5-nitrobenzimidazole, which was converted tothe corresponding amines in hydrogenation (H₂/Pd-C). The amine mixture(3.4 g, 19 mmol) in 50 ml of AcOH was added solution of Br₂ in AcOHuntil it produces a precipitation. The reaction mixture was concentratedin vacuo to provide a brown solid which was subjected to columnchromatography (5% NH₃ sat'd isopropanol/CHCl₃) to provide 0.42 g (1.6mmol) of 3-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole and 0.57 g (2.2mmol, 11%) of 1-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole.

1-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of 1-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole (0.25 g, 1.4mmol) and ISA (0.35 g, 2.6 mmol) provided 0.21 g (0.87 mmol, 62%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallization from isopropanol to afford0.17 g (28%) of the product as a white solid: mp 141-143° C.; Anal.Calc. for C₁₂H₁₄N₅OBr.1.0C₄H₄O₄ requires C, 43.55; H, 4.12; N, 15.87.Found: C, 44.14; H, 4.03; N, 15.53.

EXAMPLE 393-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#39).

A reaction of 3-(2-hydroxy-1-ethyl)-4-bromo-5-aminobenzimidazole (0.31g, 1.8 mmol) and ISA (0.52 g, 3.9 mmol) provided 0.37 g (1.6 mmol, 88%)of the desired product after column chromatography. The product obtainedwas converted to the fumarate salt and recrystallized from isopropanolto afford 0.32 g (40%) of the product as a white solid: mp 217-218° C.

EXAMPLE 401-(2-Aminoethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#40).

To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole (0.27 g, 1.3mmol) was added triphenylphosphine (0.38 g, 1.4 mmol), DEAD (0.25 ml,1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a portion and resultingmixture was stirred for 1 h at 25° C. The reaction mixture wasconcentrated in vacuo, yielding an oil which was subjected to columnchromatography (40% Hexane/EtOAc) to provide 0.36 g (1.1 mmol, 82%) of1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The nitrobenzimidazole wassubsequently subjected to hydrogenation, bromination and coupling withISA to produce 0.41 g of1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazolewhich was refluxed with 0.3 ml of hydrazine in 20 ml of MeOH for 0.5 hto yield the desired product (0.31 g, 0.96 mmol, 68% overall). Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.21 g (24%) of the product as a white foamysolid.

EXAMPLE 41 2-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#41)

2-Methyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol) in 20 ml of AcOH wasstirred at reflux for 12 h. Reaction mixture was concentrated in vacuoto yield a dark brown residue, which, in spectroscopic analysis,corresponds to 2-methyl-5-nitrobenzimidazole and was subjected to afollowing reaction without further purification. The nitrobenzimidazoleand 50 mg of 10% Pd/C were dissolved in 100 ml of MeOH and stirred for12 h under H₂. The reaction mixture was filtered and concentrated invacuo yielding 0.95 g (6.5 mmol, >95%) of brown oil which was identifiedas 2-methyl-5-aminobenzimidazole in NMR and used in a following reactionwithout further purification.

2-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of theamine (0.70 g, 4.7 mmol) and ISA (0.8 g, 5.9 mmol) was stirred at refluxfor 12 h. The reaction mixture was concentrated in vacuo to yield anoily residue which was subjected to silica gel column chromatography(NH₃ sat'd 20% MeOH/EtOAc) to yield 0.81 g (3.8 mmol, 81%) of thedesired product.

EXAMPLE 42 2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#42)

2-Methyl-4-bromo-5-aminobenzimidazole. To a solution of 0.9 g (6.1 mmol)of 2-methyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.16 ml ofBr₂ (3.1 mmol) dropwise and resulting reaction mixture was stirred for 1h at 25° C. Reaction mixture was concentrated in vacuo and purified onsilica gel column chromatography (20%) Isopropanol/EtOAC) to yield 0.56g (2.5 mmol, 41%) of the desired product.

2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. The amine(0.56 g, 2.5 mmol) and ISA (1.0 g, 7.4 mmol) were dissolved in 5 ml ofisobutanol and stirred at reflux for 12 h. The reaction mixture wasconcentrated in vacuo and subjected to column chromatography (NH₃ sat'd20% Isopropanol/EtOAC) to yield 0.72 g (2.4 mmol, >99%) of the product.The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 0.25 g (25%) of the product as awhite crystal: mp 222-224° C.; Anal. Calc. forC₁₁H₁₂N₅Br.1.0C₄H₄O₄.0.5H₂O requires C, 42.98; H, 4.09; N, 16.71. Found:C, 43.14; H, 4.03; N, 16.33.

EXAMPLE 43 2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#43)

2-Ethyl-5-aminobenzimidazole. A solution of 4-nitro-1,2-phenylenediamine(1.0 g, 6.5 mmol) in 20 ml of propionic acid was stirred at reflux for12 h. Reaction mixture was concentrated in vacuo to yield a dark brownresidue, which, in spectroscopic analysis, corresponds to2-ethyl-5-nitrobenzimidazole and was subjected to a following reactionwithout further purification. The nitrobenzimidazole and 50 mg of 10%Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H₂. Thereaction mixture was filtered and concentrated in vacuo yielding 0.95 g(6.5 mmol, >95%) of brown oil which was identified as2-ethyl-5-aminobenzimidazole in NMR and used in a following reactionwithout further purification.

2-Ethyl-4-bromo-5-aminobenzimidazole. To a solution of 1.3 g (7.7 mmol)of 2-ethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.40 ml ofBr₂ (7.5 mmol) dropwise and resulting reaction mixture was stirred for 1h at 25° C. The reaction mixture was concentrated in vacuo and purifiedon silica gel column chromatography (20% isopropanol/EtOAC) to yield 1.5g (6.3 mmol, 82%) of the desired product.

2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.

A reaction of 2-ethyl-4-bromo-5-aminobenzimidazole (1.5 g, 6.3 mmol),with ISA (2.3 g, 17 mmol) provides (1.4 g (4.5 mmol, 71%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 1.53 g (61%) of the product asa white solid: mp 186-187° C.; Anal. Calc. for C₁₂H₁₄N₅Br.1.0C₄H₄O₄requires C, 45.30; H, 4.28; N, 16.51. Found: C, 45.03; H, 4.11; N,16.88.

EXAMPLE 44 2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#44)

2-Isopropyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of isobutyricacid was stirred at reflux for 12 h. The reaction mixture wasconcentrated in vacuo to yield a dark brown residue, which was dissolvedin 100 ml of EtOAc and washed with aqueous NaHCO₃. Organic layer wasdried over MgSO₄ and concentrated in vacuo, yielding an oil which wascharacterized as 2-isopropyl-5-nitrobenzimidazole and subjected to afollowing reaction without further purification. The nitrobenzimidazoleand 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for12 h under H₂. The reaction mixture was filtered and concentrated invacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.

2-Isopropyl-4-bromo-5-aminobenzimidazole. To a solution of 0.95 g (5.4mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of AcOH was added0.19 ml (3.7 mmol) of Br₂ dropwise and resulting reaction mixture wasstirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo andpurified on silica gel column chromatography (5% MeOH/EtOAC) to yield0.89 g (3.5 mmol, 95%) of the desired product.

2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof the bromoamine (0.89 g, 3.5 mmol) and ISA (1.5 g, 11 mmol) provides0.42 g (1.3 mmol, 37%) of the expected product. The product obtained wasconverted to the fumarate salt and recrystallized from EtOH to afford0.43 g (28%) of the product as a light gray solid: mp 176-178° C.; Anal.Calc. for C₁₃H₁₆N₅Br. 1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N, 15.98.Found: C, 45.14; H, 4.39; N, 15.78

EXAMPLE 45 2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#45)

2-tert-Butyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (2.0 g, 13 mmol) in 10 ml oftrimethylacetic acid was stirred at reflux for 12 h. Reaction mixturewas concentrated in vacuo to yield a oil which was subjected to columnchromatography (CHCl₃, neat) to yield 2.2 g (10 mmol, 77%) of2-tert-butyl-5-nitrobenzimidazole. The nitrobenzimidazole and 0.5 g of10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H₂.The reaction mixture was filtered and concentrated in vacuo to provide1.9 g (10 mmol, >95%) of the desired product.

2-tert-Butyl-4-bromo-5-aminobenzimidazole. To a solution of 0.53 g (2.8mmol) of 2-tert-butyl-5-aminobenzimidazole in 50 ml of AcOH was added0.05 ml (1.0 mmol) of Br₂ dropwise and resulting reaction mixture wasstirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo andpurified on silica gel column chromatography (CHCl₃, neat) to yield 0.18g (0.67 mmol, 67%) of the desired product.

2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. A reactionof the bromoamine (0.18 g, 0.67 mmol) and ISA 0.30 g, 2.2 mmol) provides0.21 g (0.62 mmol, 93%) of the product. The product obtained wasconverted to the fumarate salt and recrystallized from EtOH to afford0.43 g (28%) of the product as a light gray solid: mp 176-178° C.; Anal.Calc. for C₁₄H₁₈N₅Br.1.0C₄H₄O₄ requires C, 47.48; H, 4.90; N, 15.48.Found: C, 45.14; H, 4.39; N, 15.78.

EXAMPLE 462-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#46)

2-Trifluoromethyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (3.0 g, 20 mmol) in 15 ml oftrifluoroacetic acid was stirred at reflux for 12 h. The reactionmixture was concentrated in vacuo to yield a oily residue, which wasdissolved in 100 ml of EtOAc and washed with aqueous NaHCO₃. The organiclayer was dried over MgSO₄ and concentrated in vacuo to provide an oilwhich was characterized as 2-trifluoromethyl-5-nitrobenzimidazole andsubjected to the following reaction without further purification. Thenitrobenzimidazole and 500 mg of 10% Pd-C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo, yielding 3.2 g (16 mmol, 80%) of the desiredproduct.

2-Trifluoromethyl-4-bromo-5-aminobenzimidazole. To a solution of 3.2 g(16 mmol) of 2-trifluoromethyl-5-aminobenzimidazole in 50 ml of AcOH wasadded 0.34 ml (6.6 mmol) of Br₂ dropwise and resulting reaction mixturewas stirred for 1 h at 25° C. The reaction mixture was concentrated invacuo and purified on silica gel column chromatography (10% MeOH/CHCl₃)to yield 1.7 g (6.2 mmol, 94%) of the desired product.

2-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole.Reaction of the bromoamine (1.3 g, 4.6 mmol) and ISA (1.5 g) provided0.39 g (1.1 mmol, 23%) of the desired product. The product obtained wasconverted to the fumarate salt and recrystallized from EtOH to afford0.40 g (21%) of the product as a light brown solid: mp 231-232° C.

EXAMPLE 47 2-Cyclopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole(#47)

2-Cyclopropyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (1.0 g, 6.6 mmol) in 15 ml ofcyclopropanecarboxylic acid was stirred at reflux for 12 h. The reactionmixture was concentrated in vacuo to yield a oil, which was dissolved in100 ml of EtOAc and washed with aqueous NaHCO₃. Organic layer was driedover MgSO₄ and concentrated in vacuo, yielding an oil which wascharacterized as 2-cyclopropyl-5-nitrobenzimidazole and subjected to afollowing reaction without further purification. The nitrobenzimidazoleand 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for12 h under H₂. The reaction mixture was filtered and concentrated invacuo to provide 0.87 g (4.9 mmol, 75%) of the desired product.

2-Cyclopropyl-4-bromo-5-aminobenzimidazole. To a solution of 0.87 g (4.9mmol) of 2-cyclopropyl-5-aminobenzimidazole in 50 ml of AcOH was added0.10 ml (1.9 mmol) of Br₂ dropwise and resulting reaction mixture wasstirred for 1 h at 25° C. The reaction mixture was concentrated in vacuoand purified on silica gel column chromatography (5% MeOH/EtOAC) toyield 0.42 g (1.8 mmol, >95%) of the desired product.

2-Cyclopropyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole. Areaction of the bromoamine (0.69 g, 2.4 mmol) and ISA (1.1 g, 8.2 mmol)provides 0.71 g (2.2 mmol, 92%) of the desired product. The productobtained was converted to the fumarate salt and recrystallized fromisobutanol to afford 0.62 g (62%) of the product as a light yellowsolid: mp 81-83° C.; Anal. Calc. for C₁₂H₁₄N₅Br.1.0C₄H₄O₄.1.0H₂Orequires C, 44.95; H, 4.44; N, 15.42. Found: C, 45.28; H, 4.35; N,14.94.

EXAMPLE 482-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#48)

2-Diphenylmethyl-5-aminobenzimidazole. A solution of4-nitro-1,2-phenylenediamine (2 g, 13 mmol) in 10 g of diphenylaceticacid(neat) was stirred at reflux for 12 h. Reaction mixture wasconcentrated in Vacuo to yield a dark brown residue, which was dissolvedin 100 ml of EtOAc and washed with aqueous NaHCO₃. Organic layer wasdried over MgSO₄ and concentrated in vacuo, yielding an oil which waspurified on column chromatography (50% Hexane/EtOAc) to yield 1.7 g (5.3mmol), 39%) of 2-diphenylmethyl-5-nitrobenzimidazole. Thenitrobenzimidazole and 250 mg of 10% Pd—C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo to provide 1.4 g (5.2 mmol, >95%) of thedesired product.

2-Diphenylmethyl-4-bromo-5-aminobenzimidazole. To a solution of 1.1 g(3.7 mmol) of 2-diphenylmethyl-5-aminobenzimidazole in 50 ml of AcOH wasadded 0.07 ml (1.3 mmol) of Br₂ dropwise and resulting reaction mixturewas stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuoand purified on silica gel column chromatography (5% MeOH/EtOAC) toyield 0.42 g (1.1 mmol, 86%) of the desired product.

2-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)benzimidzole. Areaction of the amine (1.1 g, 2.9 mmol) and ISA (1.5 g, 11 mmol)produces 0.51 g (1.1 mmol, 39%) of the expected product. The productobtained was converted to the fumarate salt and recrystallized from MeOHto afford 0.31 g (21%) of the product as a light brown solid: mp240-242° C.; Anal. Calc. for C₂₃H₂₀N₅Br.1.0C₄H₄O₄ requires C, 57.66; H,4.30; N, 12.45. Found: C, 57.58; H, 4.12; N, 12.28.

EXAMPLE 49 6-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#49)

6-Methyl-5-aminobenzimidazole. To a solution of 20 ml of fuming nitricacid was added 5-methylbenzimidazole (1.6 g, 12 mmol) slowly over 0.5 hand reaction mixture was stirred for 3 h at −15° C. During addition ofsubstrate, reaction temperature was kept below −10° C. Sticky reactionmixture was then poured into ice water to form a yellow precipitation,which was collected and dried in vacuo to provide 0.37 g (2.1 mmol, 17%of 5-methyl-6-nitrobenzimidazole. The nitrobenzimidzole was converted tothe corresponding amine (0.32 g, 95%) on hydrogenation (H₂, Pd/C).

6-Methyl-5-(2-imidazolin-2-amino)benzimidazole. The amino obtained abovewas stirred at reflux with ISA (0.96 g, 7.2 mmol) in isobutanol for 12h. Column chromatographic separation of reaction mixture (NH₃ sat'd 30%MeOH/EtOAc) produced 0.40 g (1.6 mmol, 78%) of the desired product. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom EtOH to afford 0.43 g (63%) of the product as a white solid: mp219-221° C.; Anal. Calc. for C₁₁H₁₃N₅.1.0C₄H₄O₄ requires C, 54.38; H,5.17; N, 21.14. Found: C, 54.14; H, 5.33; N, 20.84.

EXAMPLE 50 4,6-Dibromo-5-(2-imidazolin-2-ylamino)benzimidazole (#50).

To a solution of 4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.2 g,0.7 mmol) in 10 ml AcOH was added 200 mg of Hg(OAc)₂ and few drops ofBr₂. Reaction mixture was concentrated in vacuo, yielding a dark oilyresidue, which was subjected to silica gel column chromatography (NH₃sat'd 30% MeOH/EtOAc) to provide 210 mg (0.58 mmol, 86%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from EtOH to afford 0.051 g (14%) of the product as awhite solid.

EXAMPLE 51 7-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole (#51)

2,4-Dinitro-6-bromoaniline. To a solution of 2,4-dinitroaniline (2,2 g,12 mmol) in 40 ml of AcOH was added 1.0 ml of Br₂ dropwise and reactionmixture was stirred for 1 h. The reaction mixture was concentrated invacuo, yielding a dark residue which was diluted with EtOAc and washedwith aqueous NaHCO₃. Organic layer was dried over MgSO₄ and concentratedin vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-anilinewhich was characterized by NMR and used in a following reaction withoutfurther purification.

4-Bromo-6-aminobenzimidazole. A solution of 4.0 g of SnCl₂.2H₂O and 15ml of HCl was added into 2,4-dinitro-6-bromoaniline (1.8 g, 6.9 mmol)and resulting reaction mixture was stirred for 2 h at 25° C. Thereaction mixture was then basified by adding 15% aq. NaOH and extractedwith CHCl₃ several times. Combined extracts were dried over MgSO₄ andconcentrated in vacuo to produce 1.4 g (>95%) of corresponding amine.The amine was stirred at reflux in 10 ml of formic acid and 10 ml ofacetic anhydride for 12 h. The reaction mixture was concentrated invacuo, yielding oily residue which was stirred in 30 ml of HCl sat'dEtOH for 0.5 h. The oily reaction mixture after concentration wassubjected to column chromatography (5% NH₃ sat'd MeOH/EtOAc) to yield1.3 g (>95%) of the desired product.

7-Bromo-5-(2-imidazolin-2-ylamino)benzimidazole.4-bromo-6-aminobenzimidazole (0.4 g, 1.9 mmol) and ISA (1.2 g, 8.9 mmol)was dissolved in isobutanol and stirred at reflux for 12 h. Columnchromatographic separation of the reaction mixture (NH₃ sat'd 20%MeOH/EtOAc) provided 0.41 g (1.5 mmol, 78%) of the product. The productobtained was converted to the fumarate salt and recrystallized fromisopropanol to afford 0.24 g (32%) of the product as a light brownsolid: mp 217-218° C.; Anal. Calc. for C₁₀H₁₀N₅Br.1.0C₄H₄O₄ requires C,42.44; H, 3.56; N, 17.68. Found: C, 42.28; H, 3.58; N, 17.40.

EXAMPLE 52 7-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole (#52)

4-Methyl-6-aminobenzimidazole. To the solution of4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) in sealed tube with 10ml of DMF was added tetramethyltin (1.7 ml, 12 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.20 g). The resultingreaction mixture was stirred for 12 h at 140° C. and concentrated invacuo, yielding oily residue which was subjected to columnchromatography (5% MeOH/CHCl₃) to produce 0.28 g (45%) of the desiredproduct.

7-Methyl-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of theamine (0.28 g, 1.8 mmol) and ISA (0.82 g, 6.2 mmol) was stirred atreflux for 24 h. The reaction mixture was subjected to columnchromatography (30% NH₃ sat'd MeOH/EtOAc) to yield 0.23 g (57%) of theproduct. The product obtained was converted to the fumarate salt andrecrystallized form isopropanol to afford 0.24 g (40%) of the product asa light brown solid: mp 229-231° C.; Anal. Calc. for C₁₁H₁₃N₅.1.0C₄H₄O₄requires C, 54.38; H, 5.17; N, 21.14. Found: C, 54.02; H, 5.15; N,20.48.

EXAMPLE 53 7-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole (#53)

4-chloro-6-aminobenzimidazole. Methanolic solution of6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) was stirred overnight with100 mg of 10% Pd/C under H₂. Reaction mixture was filtered andconcentrated in vacuo to provide an oil which was dissolved in 10 ml ofacetic anhydride and 10 ml of formic acid and stirred at reflux for 12h. The reaction mixture was concentrated in vacuo, yielding a brown oilwhich was characterized as 4-chloro-6-foramidylbenzimidazole in NMRanalysis. The foramide was dissolved in 20 ml of HCl sat'd EtOH andstirred for 3 h at 25° C. The reaction mixture was purified in columnchromotography (5% MeOH/EtOAc) to provide 0.89 g (5.3 mmol, 48% overall)of the desired product.

7-Chloro-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of4-chloro-6-aminobenzimidazole (0.9 g, 5.4 mmol) and ISA (1.7 g, 13 mmol)was stirred at reflux for 24 h. Column chromatographic separation ofreaction mixture (30% NH₃ sat'd MeOH/EtOAc) provided 0.53 g (2.2 mmol,41%) of the product. The product obtained was converted to the fumaratesalt and recrystallized from MeOH to afford 0.41 g (22%) of the productas a light brown solid: mp 220-221° C.; Anal. Calc. forC₁₀H₁₀N₅Cl.1.0C₄H₄O₄ requires C, 47.81; H, 4.01; N, 19.91. Found: C,46.03; H, 4.14; N, 19.64.

EXAMPLE 54 7-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole (#54)

2,4-Dinitro-6-iodoaniline. To a solution of 2,4-dinitroaniline (3.0 g,16 mmol) and Hg(OAc)₂ (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g(19 mmol) of I₂ in 100 ml of AcOH dropwise and reaction mixture wasstirred for 12 h. The reaction mixture was concentrated in vacuo,yielding a dark residue which was diluted with EtOAC and washed withaqueous NaHCO₃. Organic layer was dried over MgSO₄ and concentrated invacuo to produce dark residue which was subjected to columnchromatography (CHCl₃, neat) to provide 4.1 g (13 mmol, 81%) of2,4-dinitro-6-iodoaniline.

7-Iodo-5-aminobenzimidazole. A solution of 10 g of SnCl₂.2H₂O and 20 mlof HCl was added into 2,4-dinitro-6-iodoaniline (4.1 g, 13 mmol) andresulting reaction mixture was stirred at reflux for 48 h. The reactionmixture was then basified by adding 15% aq. NaOH and extracted withCHCl₃ several times. Combined extracts were dried over MgSO₄ andconcentrated in vacuo, yielding oily residue which was subjected tocolumn chromatography (5% MeOH/EtOAc) to yield 1.1 g (4.4 mmol, 33%) ofthe amine. The amine was stirred at reflux in 10 ml of formic acid and10 ml of acetic anhydride for 12 h. The reaction mixture wasconcentrated in vacuo to yield an oily residue which was stirred in 30ml of HCl sat'd EtOH for 2 h. The oily reaction mixture afterconcentration was subjected to column chromatography (5% NH₃ sat'dMeOH/EtOAc) to provide 0.69 g (2.7 mmol,60%) of the desired product.

7-Iodo-5-(2-imidazolin-2-ylamino)benzimidazole. A solution of4-iodo-6-aminobenzimidazole (0.69 g, 2.7 mmol) and ISA (0.90 g, 6.7mmol) was stirred at reflux for 12 h. Column chromatographic separation(30% NH₃ sat'd MeOH/EtOAc) of resulting reaction mixture provided 0.88 g(>99%) of the product. The product obtained was recrystallized fromisopropanol to afford 0.56 g (64%) of the product as a light brownsolid: mp 180-181° C.

EXAMPLE 55 7-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole (#55)

2,4-Diamino-6-ethylaniline. A solution of 2,4-dinitro-6-bromoaniline(1.6 g, 6.1 mmol), tetraethyltin (2.4 ml, 12.2 mmol) and Cl₂Pd(PPh₃)₂(100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reactionmixture was concentrated in vacuo, yielding an oil which was purified onsilica gel column chromatography (CH₂Cl₂, neat) to provide 0.68 g (3.2mmol, 53%) of 2,4-dinitro-6-ethylaniline, which was converted to thediamine (0.45 g, 95%) on hydrogenation (H₂/Pd—C).

7-Ethyl-5-aminobenzimidazole. The amine (0.46 g, 3.1 mmol) was stirredat reflux in formic acid for 12 h. The reaction mixture was concentratedin vacuo to provide an oil, which was dissolved in 50 ml of HCl sat'dEtOH and stirred for 1 h. The reaction mixture was concentrated invacuo, yielding an oil, which was subjected to column chromatography(EtOAc, neat) to provide 0.23 g (1.5 mmol, 47%) of the desired product.

7-Ethyl-5-(2-imidazolin-2-ylamino)benzimidazole. The benzimidazole (0.23g, 1.5 mmol) and ISA (0.67 g, 5.0 mmol) was dissolved in isobutanol andstirred at reflux for 12 h. Column chromatographic separation ofreaction mixture (NH₃sat'd 20% MeOH/EtOAc) provided 0.30 g (1.4 mmol,92%) of the product. The product obtained was converted to the fumaratesalt and recrystallized from isopropanol to afford 0.17 g (46%) of theproduct as a light brown solid: mp 203-205° C.; Anal. Calc. forC₁₂H₁₅N₅.1.0C₄H₄O₄ requires C, 55.65; H, 5.55; N, 20.28. Found: C,55.90; H, 5.43; N, 19.87.

EXAMPLE 56 7-Butyl -5-(2-imidazolin-2-ylamino)benzimidazole (#56)

2,4-Diamino-6-butylaniline. A solution of 2,4-dinitro-6-bromoaniline(2.0 g, 7.6 mmol), tetrabutyltin (5.3 ml, 15.2 mmol) and Cl₂Pd(PPh₃)₂(100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reactionmixture was concentrated in vacuo, yielding an oil which was purified onsilica gel column chromatography (CH₂Cl₂, neat) to provide 0.50 g (2.0mmol, 27%) of 2,4-dinitro-6-butylaniline, which was converted to thediamine (0.38 g, >95%) on hydrogenation (H₂/Pd—C).

7-Butyl-5aminobenzimidazole. The amine (0.46 g, 3.1 mmol) was stirred atreflux in formic acid for 12 h. reaction mixture was concentrated invacuo to provide an oil, which was dissolved in 50 ml of HCl sat'd EtOHand stirred for 1 h. The reaction mixture was concentrated in vacuo,yielding an oil, which was subjected to column chromatography (EtOAc,neat) to provide 0.11 g (0.86 mmol, 28%) of the desired product.

7-Butyl-5-(2-imidazolin-2-ylamino)benzimidazole. The benzimidazole (0.11g, 0.86 mmol) and ISA (0.25 g, 1.9 mmol) was dissolved in disobutanoland stirred at reflux for 12 h. Column chromatographic separation ofreaction mixture (NH₃ sat'd 20% MeOH/EtOAc) provided 0.21 g (0.81 mmol,95%) of the product. The product obtained was converted to the fumaratesalt and recrystallized from isopropanol to afford 0.17 g (45%) of theproduct as a light brown solid: mp 115-117° C.; Anal. Calc. forC₁₄H₁₉N₅.1.5C₄H₄O₄ requires, C, 55.68; H, 5.84; N, 16.23. Found: C,54.90; H, 5.84; N, 15.99.

EXAMPLE 57 7-Phenyl-5-(2-imidazolin-2-ylamino)benzimidazole (#57)

2,4-Diamino-6-phenylaniline. A solution of 2,4-dinitro-6-bromoaniline(2.5 g, 9.5 mmol), tetraphenylltin (6.1 g, 14.3 mmol) and Cl₂Pd(PPh₃)₂(100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reactionmixture was concentrated in vacuo, yielding an oil which was purified onsilica gel column chromatography (CH₂Cl₂, neat) to provide 1.0 g (3.8mmol, 41%) of 2,4-dinitro-6-phenylaniline, which was converted to thediamine (0.72 g, >95%) on hydrogenation (H₂/Pd—C).

7-Phenyl-5-aminobenzimidazole. The amine (0.72 g, 3.8 mmol) was stirredat reflux in formic acid for 12 h. The reaction mixture was concentratedin vacuo to provide an oil, which was dissolved in 50 ml of HCl sat'dEtOH and stirred for 1 h. The reaction mixture was concentrated invacuo, yielding an oil, which was subjected to column chromatography(EtOAc, neat) to provide 0.48 g (2.3 mmol, 60%) of the desired product.

7-Phenyl-5-(2-imidazolin-2-ylamino)benzimidazole. The benzimidazole(0.48 g, 2.3 mmol) and ISA (1.0 g, 7.5 mmol) was dissolved in isobutanoland stirred at reflux for 12 h. Column chromatographic separation ofreaction mixture (NH₃ sat'd 20% MeOH/EtOAc) provided 0.64 g (0.23 mmol,≦95%) of the product. The product obtained was converted to the fumaratesalt and recrystallized from isopropanol to afford 0.25 g (24%) of theproduct as a light brown solid: mp 149-151° C.; Anal. Calc. forC₁₆H₁₅N₅.1.5C₄H₄O₄ requires C, 58.53; H, 4.69; N, 15.51. Found: C,57.79; H, 4.80; N, 15.31.

EXAMPLE 58 4,7-Dibromo-5-(2-imidazolin-2-ylamino)benzimidazole (#58)

To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g,2.10 mmol) in 10 ml of AcOH was added Br₂ (0.057 ml, 1.1 mmol) in aportion. The resulting reaction mixture was stirred for 1 h at 25° C.Concentration of reaction mixture in vacuo yields a brown oil which wassubjected to column chromatography (30% NH_sat'd MeOH/EtOAc) to provides0.28 g (1.5 mmol, 71%) of the desired product. The product obtained wasrecrystallized from MeOH to afford 0.22 g (56%) of the product as alight brown solid: mp320-321° C.; Anal. Calc. for C₁₀H₉N₅Br₂ requires C,33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.

EXAMPLE 59 4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)benzimidazole(#59)

4-Bromo-7-methyl-5-aminobenzimidazole. A solution of4,7-dibromo-5-aminobenzimidazole (1.5 g, 5.1 mmol) in 10 ml of DMF wastransferred into pressure bottle under Ar₂. To the solution was addedtetramethyltin 3.6 ml, 20 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg). The resulting reaction mixture wasstirred at 140° C. for 24 h and concentrated in vacuo, yielding a darkoil which was subjected to column chromatography (40% EtOAC/CHCl₃) toyield 0.34 g (1.5 mmol, 29%) of the desired product as well as 0.75 g of4,7-dimethyl-5-aminobenzimidazole.

4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)benzimidazole.

A solution of the amine (0.34 g, 1.5 mmol) and ISA (0.69 g, 5.1 mmol) in10 ml of isobutanol was stirred at reflux for 12 h. The resultingreaction mixture was purified on column chromatography (30% NH₃ sat'dMeOH/EtOAc) to yield 0.25 g (0.86 mmol, 57%) of the desired product. Theproduct obtained was recrystallized from MeOH to afford 0.13 g (30%) ofthe product as a light brown solid: mp 242-244° C.; Anal. Calc. forC₁₁H₁₂N₅Br requires C, 44.91; H, 4.11; N, 23.81. Found: C, 43.93; H,4.05; N, 23.01.

EXAMPLE 60 4-Bromo-7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole(#60).

To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61g, 2.6 mmol) in 10 ml of AcOH was added 0.3 ml of Br₂. Resultingreaction mixture was stirred for 12 h at 25° C. and concentrated invacuo, yielding an oil, which was subjected to column chromatography(NH₃ sat'd 30% MeOH/EtoAc) to yield 0.23 g (0.85 mmol, 33%) of thedesired product. The product obtained was converted to the fumarate saltand recrystallized from MeOH to afford 0.12 g (12%) of the product as alight yellow solid: mp 244-246° C.; Anal. Calc. forC₁₀H₉N₅BrCl.1.0C₄H₄O₄.0.5H₂O requires C, 37.77; H, 3.17; N, 18.35.Found: C, 37.75; H, 3.08; N, 18.21.

Pharmacological Profiles of the Compounds in Cloned Human AdrenergicReceptors

Binding and functional assays were performed using stably transfectedhuman alpha adrenergic receptors. Equilibrium competition binding assayswere performed with membrane preparations from cultured LM(tk-) cellsstably transfected with the cloned human adrenoceptor subtypes exceptfor α_(2b), which was expressed in Y-1 cells, using [³H] prazosin for α₁receptors and [³H] rauwolscine for α₂ receptors.

EXAMPLE 61 Protocol for the determination of the potency of α₂ agonists

The activity of the compounds at the different receptors was determinedin vitro using cultured cell lines that selectively express the receptorof interest. These cell lines were prepared by transfecting the clonedcDNA or cloned genomic DNA or constructs containing both genomic DNA andcDNA encoding the human alpha adrenergic receptors as described below.Table 1 shows the binding and functional activities at cloned humanalpha adrenergic receptors.

α_(2A) Human Adrenergic Receptor: The entire coding region of α_(2A)(1350 bp), including 1.0 kilobasepairs of 5′ untranslated sequence(5′UT) and 100 bp of 3′ untranslated sequence (3′UT) was cloned into theSmal site of the eukaryotic expression vector pCEXV-3. The insulthousing this coding region was an @2.5 kb Kpnl/HindIII human placentagenomic fragment which was end-blunted by either T₄ polymerase or Klenowfragment of DNA polymerase. Stable cell lines were obtained bycontransfection with the Plasmid pGCcos3neo (plasmid containing theα_(2A) receptor gene) and the plasmid pGCcos3neo (plasmid containing theaminoglycoside transferase gene) into LM(tk-), CHO, and NIT3t3 cells,using calcium phosphate technique. The cells were grown, in a controlledenvironment (37° C., 5% CO₂), as monolayers in Dulbecco's modifiedEagle's Medium (GIBCO, Grand Island, N.Y.) containing 25 mM glucose andsupplemented with 10% bovine calf serum, 100 units/ml penicillin g, and100 μg/ml streptomycin sulfate. Stable clones were then selected forresistance to the antibiotic G-418 (1 mg/ml), and membranes wereharvested and assayed for their ability to bind [³H] rauwolscine asdescribed below (see “Radioligand Binding Assays”)

α_(2B) Human Adrenergic Receptor: The entire coding region of α_(2B)(1350 bp), including 393 bp of 5′-untranslated sequence and 11 bp of 3′untranslated sequence, was cloned into the eukaryotic expression vectorpcEXV-3 (Weinshank et al., U.S. Pat. No. 5,053,337, issued Oct. 1,1991). Stable cell lines were selected as described above.

α_(2C) Human Adrenergic Receptor: The entire coding region of α_(2C)(1383 bp), including 2 bp of 5′ UT and 400 bp of 3′ UT, was cloned intothe Smal site of the eukaryotic expression vector pCEXV-3. The inserthousing this coding region was an @1.8 kb Ncol/EcoRI human spleengenomic fragment which was end-blunted by either T₄ polymerase or Klenowfragment of DNA polymerase. Stable cell lines were selected as describedabove.

Radioligand Binding Assays: Transfected cells from culture flasks werescraped into 5 ml of 5 mM Tris-HCl, 5 mM EDTA, pH 7.5, and lysed bysonication. The cell lysates were centrifuged at 1000 rpm for 5 min at4° C., and the supernatant was centrifuged at 30,000×g for 20 min at 4°C. The pellet was suspended in 50 mM Tris-HCl, 1 mM MgCl₂, and 0.1%ascorbic acid at pH 7.5. Binding of α₂ antagonist [³H] rauwolscine (0.5mM) to membrane preparations of LM(tk-) cells was done in a final volumeof 0.25 ml and incubated at 37° C. for 20 min. Nonspecific binding wasdetermined in the presence of 10 μM phentolamine. The reaction wasstopped by filtration through GF/B filters using a cell harvester.Inhibition experiments, routinely consisting of 7 concentrations of thetested compounds, were analyzed using a non-linear regressioncurve-fitting computer program to obtain Ki values.

Measurement of Agonist Activity: The agonist activity (expressed aspEC₅₀) was measured as a function of the ability to inhibit theforskolin-stimulated synthesis of cyclic adenosine monophosphate (cAMP).The stably transfected cells were incubated in Ham's F10 with 5 mMtheophylline, 10 mM HEPES, 10 μM pargyline, and/or appropriateconcentrations of forskoliin for 20 min at 37° C. in 5% CO₂. The testedcompounds were then added to a final concentration of 0.001 nM to 1 μMand incubated for an additional 15 min at 37° C. in 5% CO₂. The mediumwas aspirated and the reaction was stopped by the addition of 100 mMHCl. To demonstrate competitive antagonism, a dose-response curve fornorepinephrine was measured in parallel, using a fixed dose ofnorepinephrine (0.32 μM). The plates are stored at 4° C. for 15 min andassayed to determine the linear concentration of cAMP. The appropriatedilution is interpolated from the standard curve of cold cAMP. Theassessment of cAMP formation is determined by radioimmunoassay (cAMPradioimmunoassay kit; Advanced Magnetics, Cambridge Mass.).Radioactivity was quantified using a Packard COBRA Auto Gamma counter,equipped with data reduction software.

α_(1A) Human Adrenergic Receptor: The entire coding region of α_(1A)(1719 bp), including 150 bp of 5′ untranslated sequence (5′UT) and 300bp of 3′ untranslated sequence (3′UT), was cloned into the BamHI andClaI sites of the polylinker-modified eukaryotic expression vectorpCEXV-3, called EXJ.HR (Bard et al, International Publication No.WO94/08040, published Apr. 14, 1994). The construct involved theligation of partial overlapping human lymphocyte genomic and hippocampalcDNA clones: 5′ sequences were contained on a 1.2 kb SmaI-XhoI genomicfragment (the vector-derived BamHI site was used for subcloning insteadof the internal insert-derived SmaI site) and 3′ sequences werecontained on 1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was from thevector polylinker). Stable cell lines were selected as described above.

α₁₉ Human Adrenergic Receptor: The entire coding region of α_(1B) (1563bp), including 200 basepairs and 5′ untranslated sequence (3′ UT) and600 bp of 3′ untranslated sequence (3′ UT), was cloned into the EcoRIsite of pCEXV-3 eukaryotic expression vector (Bard et al, InternationalPublication No. WO 94/08040, published Apr. 14, 1994). The constructinvolved ligating the full-length containing EcoRI brainstem cDNAfragment from ZapII into the expression vector. The stable cell lineswere selected as described above.

α_(1C) Human Adrenergic Receptor: The entire coding region of α_(1C)(1401 bp), including 400 basepairs of 5′ untranslated sequence (5′ UT)and 200 p of 3′ untranslated sequences (3′ UT), was cloned into the KpnIsite of the polylinker-modified pCEXV-3-derived eukaryotic expressionvector, EXJ.RH (Bard et al, International Publication No. WO 94/08040,published Apr. 14, 1994). The construct involved ligation three partialoverlapping fragments: a 5′ 0.6 kb HincII genomic clone, a central 1.8EcoRI hippocampal cDNA clone, and a 3′ 0.6 Kb PstI genomic clone. Thehippocampal cDNA fragment overlaps with the 5′ and 3′ genomic clones sothat the HincII and PstI sites at the 5′ and 3′ ends of the cDNA clone,respectively, were utilized for ligation. This full-length clone wascloned into the KpnI site of the expression vector, using the 5′ and 3′KpnI sites of the fragment, derived from vector (i.e., pBluescript) and3′-untranslated sequences, respectively. Stable cell lines were selectedas described above.

TABLE 1 Binding and Functional Activities at Cloned HumanAlpha-Adrenergic Receptors Alpha-2 Alpha-1 Ex A B C A B C 1 pKi 7.747.13 7.15 5.17 4.61 5.28 pEC50 7.24 7.35 8.56 I.A 1.00 1.00 1.00 2 pKi8.41 7.69 7.01 6.02 5.23 5.77 pEC50 9.53 7.73 8.93 I.A 1.00 1.00 1.00 3pKi 8.12 7.81 7.00 6.27 5.09 5.72 pEC50 9.18 7.90 9.25 I.A 1.00 1.001.00 4 pKi 8.51 8.04 7.59 6.22 5.56 6.14 pEC50 9.41 8.01 9.45 I.A 1.001.00 1.00 5 pKi 8.45 7.51 7.62 6.27 5.74 5.65 pEC50 9.05 7.33 8.87 I.A1.00 1.00 1.00 6 pKi 8.33 7.65 7.32 ND ND ND pEC50 8.17 7.65 8.40 I.A1.00 1.00 1.00 7 pKi 8.45 7.55 7.38 6.57 5.91 5.75 pEC50 8.14 6.70 8.21I.A 1.00 1.00 1.00 8 pKi 7.59 7.30 6.92 6.17 5.58 5.75 pEC50 6.87 6.637.68 I.A 0.90 0.80 1.00 9 pKi 7.74 7.33 6.81 5.56 4.87 5.17 pEC50 6.657.23 7.92 I.A 1.00 1.00 1.00 10 pKi 8.23 7.55 7.81 6.21 5.42 6.07 pEC508.52 6.99 8.63 I.A 1.00 1.00 1.00 11 pKi 7.09 6.65 5.95 5.00 4.45 5.24pEC50 NA NA NA I.A 12 pKi 8.20 7.84 7.59 7.02 6.46 6.46 pEC50 7.27 7.517.76 I.A 1.00 1.00 1.00 13 pKi 7.85 6.44 6.40 4.98 4.03 5.53 pEC50 NA NANA I.A 14 pKi 8.02 6.66 6.64 5.63 4.69 6.21 pEC50 6.60 NA NA I.A 1.00 15pKi 6.94 6.14 6.06 5.19 4.46 5.31 pEC50 NA NA NA I.A 16 pKi 8.25 7.917.38 7.26 6.29 6.38 pEC50 6.40 NA NA I.A 1.00 17 pKi 7.39 6.18 6.08 4.984.35 5.04 pEC50 NA NA NA I.A 1.00 18 pKi 8.35 6.43 6.55 5.57 4.70 6.05pEC50 7.08 NA NA I.A 0.80 19 pKi 8.33 6.67 6.89 ND ND ND pEC50 6.31 NANA I.A 0.70 20 pKi 6.62 6.14 6.20 4.83 4.23 4.95 pEC50 NA NA NA I.A 21pKi 8.19 7.67 7.26 6.13 5.33 5.92 pEC50 6.60 NA NA I.A 0.90 22 pKi 8.106.37 6.74 4.98 3.98 5.73 pEC50 NA NA NA I.A 23 pKi 7.90 6.51 6.64 5.304.42 6.42 pEC50 6.16 NA NA I.A 0.90 24 pKi 8.48 7.89 7.47 6.51 5.31 6.60pEC50 7.34 NA NA I.A 1.00 25 pKi 7.79 6.19 6.36 5.21 4.35 5.01 pEC50 NANA NA I.A 26 pKi 7.93 6.25 6.59 5.05 4.24 5.02 pEC50 NA NA NA I.A 27 pKi7.03 5.99 6.14 5.08 4.47 5.16 pEC50 NA NA NA I.A 28 pKi 8.41 7.38 7.026.18 4.98 5.42 pEC50 NA NA NA I.A 29 pKi 7.58 6.44 6.31 6.04 4.68 5.85pEC50 NA NA NA I.A 30 pKi 7.76 6.78 6.51 ND ND ND pEC50 NA NA NA I.A 31pKi 8.18 7.43 7.41 6.59 5.67 6.43 pEC50 NA NA NA I.A 32 pKi 7.96 7.306.79 5.43 4.48 5.41 pEC50 NA NA NA I.A 33 pKi 8.47 7.86 6.79 5.74 4.485.84 pEC50 NA NA NA I.A 34 pKi 7.42 7.05 6.73 5.59 4.92 5.87 pEC50 NA NANA I.A 35 pKi 8.46 7.80 7.77 6.51 5.71 6.10 pEC50 NA NA NA I.A 36 pKi8.02 6.97 6.78 6.09 4.96 5.19 pEC50 8.26 6.55 NA I.A 0.60 0.60 37 pKi8.18 7.09 6.93 ND ND ND pEC50 7.69 NA 7.28 I.A 0.60 0.50 38 pKi 7.416.28 5.89 5.14 4.76 5.17 pEC50 7.45 6.80 6.44 I.A 1.00 0.80 1.00 39 pKi7.36 6.31 6.21 5.80 4.96 5.32 pEC50 7.61 NA NA I.A 0.90 40 pKi 6.40 6.025.55 5.03 4.57 5.04 pEC50 6.14 NA NA I.A 0.80 42 pKi 7.99 7.63 6.67 5.795.07 5.09 pEC50 7.63 7.01 NA I.A 1.00 0.60 43 pKi 8.14 7.47 6.74 5.765.16 5.67 pEC50 7.64 6.79 7.09 I.A 1.00 0.80 0.90 44 pKi 8.53 7.33 6.675.69 5.23 5.51 pEC50 8.40 7.04 6.74 I.A 1.00 0.80 0.80 45 pKi 8.07 7.086.53 5.34 4.94 5.66 pEC50 7.28 6.07 7.92 I.A 1.00 0.70 0.60 46 pKi 7.346.98 5.83 5.15 4.55 4.97 pEC50 7.41 6.23 7.19 I.A 1.00 0.80 0.90 47 pKi8.17 7.35 6.65 ND ND ND pEC50 7.33 6.94 7.34 I.A 1.00 0.80 0.80 48 pKi7.11 6.18 6.61 5.91 7.31 6.92 pEC50 NA 6.70 8.87 I.A 0.80 0.60 49 pKi7.71 7.44 6.67 ND ND ND pEC50 7.04 NA 7.65 I.A 0.80 1.00 50 pKi 8.168.63 7.61 7.45 6.78 6.11 pEC50 7.80 7.68 7.15 I.A 1.00 0.90 1.00 51 pKi7.58 7.56 6.91 ND ND ND pEC50 7.01 7.05 8.37 I.A 0.90 0.60 1.00 52 pKi7.61 7.11 6.90 ND ND ND pEC50 7.09 7.14 8.26 I.A 0.90 0.80 1.00 53 pKi7.83 7.74 7.05 6.51 5.72 6.00 pEC50 7.24 7.74 8.97 I.A 1.00 1.00 1.00 54pKi 7.31 7.56 6.70 ND ND ND pEC50 5.90 6.88 7.69 I.A 0.70 0.60 0.90 55pKi 7.36 6.68 6.37 ND ND ND pEC50 7.29 NA 6.79 I.A 0.60 0.80 56 pKi 7.666.74 6.69 5.90 5.29 6.23 pEC50 6.30 6.86 7.89 I.A 0.70 0.30 1.00 57 pKi7.78 7.22 6.87 ND ND ND pEC50 NA 5.07 7.82 I.A 0.50 1.00 58 pKi 8.898.76 7.51 ND ND ND pEC50 8.61 7.55 8.49 I.A 1.00 0.50 1.00 59 pKi 9.018.10 7.78 ND ND ND pEC50 9.08 7.39 8.89 I.A 1.00 0.90 1.00 60 pKi 9.059.33 7.79 6.85 6.5  6.32 pEC50 9.23 7.75 9.4  I.A 1   0.9 1   C pKi 8.038.09 7.52 6.29 5.62 6.01 pEC50 8.09 6.79 7.26 I.A 1   1   1   NA: NotActive ND: Not Determined C: Clonidine

The protocols used to obtain these data are described in Example 61.

EXAMPLE 62 Assay to measure analgesic activity of test compounds

Warm-Water Trail Withdrawal Assay (Butelman, E. R.; Woods, J. H. J.Pharmacol. Exp. Therapeut. 1993, 264, 7620)

Subjects. Adult rhesus monkeys (Macaca mulatta) of either sex werehoused individually with free access to water. They were fed fresh fruitweekly and approximately 40 biscuits (Purina Monkey Chow) daily.

Apparatus and procedure. Tail withdrawal latencies were timed manuallyusing a microprocessor (IBM PCjr) via a push bottom switch. Monkeys wereseated in primate restraining chairs, and the lower portion of theshaved tail (approximately 10 cm) was immersed in a thermos flaskcontaining water maintained at either 40, 50 or 55° C. A maximum allowedlatency of 20 seconds was recorded if the monkeys failed to remove theirtails by this time. Sessions began with control determinations at eachwater temperature, presented in a varied order between the subjects. Inorder for a subject to be used, its withdrawal latency at 40° C. had toreach 20 seconds. After control determinations, drugs were administeredevery 30 minutes using a cumulative dosing procedure in which dosesincreased in 0.25 or 0.5 log units with each cycle. Fifteen minutesafter each injection, the subjects were tested at the three temperaturesin varying order, with tests being separated from each other byapproximately 2 minutes. In time course studies, a single drug dose wasadministered after control determination, with testing following at 30minutes intervals.

Design. Clonidine and compound 4 were studied up to doses that producednear maximal withdrawal latencies in 55° C. water. The same threesubjects were studied in all the above experiments.

Sedation and Muscle Relaxation

Procedure. Monkeys were trained to receive subcutaneous injections whilein their home cages; they were rated by one non-blind observer familiarwith the individual subjects, according to modified rating scales forsedation and muscle relaxation (Table 2). Separate scales describeincreasing degress of sedation (as measured by responsiveness tostimuli) and muscle relaxation (as observed through changes in posture).Animals were injected in a cumulative dosing procedure with a 30 minuteinterinjection interval; observer rating on both scales took placeapproximately 15 minutes after each injection.

Design. Clonidine (0.032-1.0 mg/kg) and compound 4 (0.1-3.2 mg/kg) werestudied using a cumulative dosing procedure. The same three monkeys weretypically studied under each se of conditions.

Results: Using the procedures described above, compound 4 was found tobe an effective analgesic agent with decreased sedation relative to thereference compound, clonidine.

TABLE 2 Modified sedation and muscle relaxation rating scales GradeSedation 0 No observable sedation 1 Monkey appears to stare into space 2Monkey is inattentive to ordinary movements of observer 3 Monkeyresponds only to loud noises in the room 4 Monkey responds only toopening of cage latch 5 Monkey responds only to loud noises near its ear6 Monkey responds only to touch Muscle Relaxation 0 No observable musclerelaxation 1 Slight facial relaxation, jaw slackening, shoulder droop 2Pronounced facial relaxation, jaw slackening, shoulder droop 3 Monkeymust brace itself to sit up 4 Monkey cannot sit up

What is claimed is:
 1. A compound having the structure:

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 2. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound of claim 1 and a pharmaceutically acceptablecarrier.
 3. A method of treating nasal congestion in a subject whichcomprises administering to the subject an amount of the compound ofclaim 1 effective to treat the subject's nasal congestion.